It has long been recognized that immune inflammation comes about by a combination of antigen-specific and non-specific immune responses to a given stimulus. Antigen-specific responses comprise in part, T and B cell recognition of self and/or exogenous proteins or peptides, or even mixtures of lipids, carbohydrates and peptides, either soluble, complexed to antibodies, or processed into immunogenic peptides (i.e. epitopes) by antigen presenting cells. Recognition of an antigen leads to a response by the specific effector B or T cells and consists of a combination of cell proliferation, soluble mediator (i.e. cytokines) and/or effector (i.e. antibodies) secretion, and the expression of transmembrane proteins which govern the intensity and duration of the response through direct cell to cell contact or by soluble mediators. Under physiologic conditions, such antigen-specific responses are usually self-limited and appear to control non-specific immune mechanisms. The recognition of an antigen can also lead directly to interference with downstream events, through anergy or clonal deletion of specific cells.
Many treatment regimens have been developed for the treatment of rheumatoid arthritis and other autoimmune diseases with which immune inflammation is a complication. For example, “biologic therapies” have brought about numerous advances in the therapeutic approach to these diseases. Such therapies often include use of genetically engineered proteins. For example, monoclonal antibodies and receptor-immunoglobulin fusion proteins designed to modulate specific underlying autoimmune processes can be used and often allow for avoidance of certain problematic effects such as generalized immunosuppression. Such therapies also include use of compounds that interfere with the “trimolecular complex” that comprises the major histocompatibility complex II-Antigen-T cell receptor interactions.
Other treatment regimens are designed to block secondary signals for T cell activation and T cell interaction by using antigen-presenting cells, and cytokine agonists as well as antagonists.
Still other treatment therapies include regimens designed to affect tumor necrosis factor alpha (TNFα), which is a pivotal cytokine in the inflammatory process. For example, in one such regimen, anti-TNF reagents are used to interfere with the TNF pathway to provide short-term clinical efficacy and tolerability. Such anti-TNF reagents include infliximab which is a chimeric monoclonal anti-TNFα, soluble TNFα receptors, etanercept, and talidomide. Such therapeutic compounds also affect cytokines, for example, interleukin-1 (IL-1), wherein production of IL-1 in vivo is blocked. The blocking of IL-1 production may have beneficial effects, although the nature of such effects is still to be determined.
The use of etanercept, a fusion protein consisting of the extracellular ligand binding domain of the 75 kD receptor for TNFα and the constant portion of human IgG1, alone or in combination with methotrexate for treating patients having active rheumatoid arthritis (defined by the American College of Rheumatology (ACR) as functional class I to III) and who had previously failed to respond to treatment with greater than or equal to one disease-modifying antirheumatic drug (DMARD), produced improvements in all core ACR measures of disease activity.
Although the various above stated therapy regimens have shown a degree of success in treating autoimmune diseases, problems associated with long-term administration of such biological agents are not yet known. Both IL-1 and TNFα play important roles in normal host defenses and complications from blocking their production or effects may develop in patients. Ultimately, there is a need for careful evaluation of such therapeutics in long-term studies. There is also concern that such therapies may increase the rate of serious infections and allow for a reduced degree of control over neoplastic cells, especially in patients with severe disease. The development of antiglobulin responses to injected monoclonal antibodies and poor pharmacokinetics of low molecular-weight inhibitors are additional problems.
Other advances in treatment of autoimmune diseases include the limited use of combination-oriented therapies. For example, a treatment regimen for experimental autoimmune encephalomyelitis (EAE) has been tested using antigen-specific immunotherapy combined with cytokine therapy. In this example, local gene delivery of the interleukin-4 (IL-4) gene was administered with a tolerizing DNA vaccination; the DNA of the vaccine encoding a self-peptide proteolipid protein. This therapy demonstrated that co-delivery of two different DNAs provides protective immunity against EAE and reverse established EAE by the expression of IL-4 from the delivered naked DNA, which is secreted and acts locally on autoreactive T cells, causing the cells to shift their cytokine profile to Th 2. This treatment strategy therefore combined the antigen-specific effects of DNA vaccination and the beneficial effects of local gene delivery. However, the methodology of the treatment provided no directed control over the desired immune modulation. The ultimate efficacy of such a regimen is unknown because there is no demonstration of the capability to control the modulation of immune response.
Thus, a need exists for additional combination therapies that can more directly provide immune modulation in the treatment of immune diseases without compounding side effects. The present invention satisfies this need and provides additional advantages through a broad-based approach to immunotherapy for immune mediated diseases that allows for the controlled modulation of pathogenic immune response using a combination of epitope-specific and cytokine or anticytokine immunotherapy.